Group B streptococci (GBS) are important human pathogens. These bacteria are increasingly being recognized as disease causing agents in adults, particularly in immunocompromised individuals; however, it is as the infectious agent of over 40% of all cases of neonatal sepsis in the U.S. which caused GBS to be recognized by the National Academy of Sciences in 1985 as the fourth most important cause of preventable infectious morbidity in this country. There are over 12,000 cases of GBS sepsis in the U.S. annually, resulting in over 2,500 infant deaths and 1,350 cases of permanent neurologic damage. In addition, pregnancy-related morbidity occurs in nearly 50,000 women each year. One recent review article estimated the direct cost per year of GBS disease in this country at over $726 million. No GBS vaccine is currently available, yet it has been estimated that over 94% of the cost due to group B streptococcal disease could potentially be avoided by the development of an effective maternal vaccine.
In addition to the group B specific carbohydrate antigen which delineates GBS from other streptococcal species, these bacteria are serotyped based on the presence of one of seven known type-specific carbohydrate antigens expressed on their surfaces. These are called Ia, Ib, II, III, IV, V, and VI. In addition, a number of protein antigens known collectively as C proteins have been identified. These are designated as alpha, beta, gamma, and delta. The genes encoding the alpha and beta antigens have been cloned (Cleat and Timmis, 1987; Michel et al., 1991) and sequenced (Jerlstrom et al., 1991; Heden et al., 1991; Michel et al., 1992), and the beta antigen has been shown by a number of researchers to interact specifically, but in a non-immune manner, with the Fc region of human IgA (Russell-Jones and Gotschlich, 1984; Russell-Jones et al., 1984; Brady et al., 1989; Anthony et al., 1990; Lindahl et al., 1990; Kvam et al., 1992). The distribution of specific C protein antigens among strains of particular carbohydrate serotypes has been partially described in the literature and is complex.
A number of research groups have reported that greater than half of all cases of neonatal sepsis are caused by type III organisms, whereas type III organisms account for less than 25% of the organisms isolated from healthy colonized infants and pregnant women. There is a greater interest in protection against serotype III GBS, although none of the serotypes are considered to be benign. The only C protein antigen commonly associated with type III GBS is the delta antigen (Brady et al., 1989; Chun et al., 1991).
Low levels of maternal IgG antibodies to GBS serotype-specific carbohydrate antigens have been shown to be correlated with disease susceptibility in neonates (Baker et al., 1978; Fisher et al., 1983). Unfortunately, many carbohydrate antigens are poorly immunogenic in humans. This is known to be true of GBS type specific carbohydrates with the possible exception of the type II polysaccharide. Development of a vaccine that is effective against multiple serotypes of GBS is considered to be of paramount importance in disease prevention. The full-length GBS beta antigen is a polypeptide of approximately 130,000 daltons. It has been reported to be immunogenic and to elicit the formation of protective antibodies in animal models (Michel et at, 1991; Madoff et al., 1992). However, the potential for the use of the .beta. antigen as a vaccine is substantially compromised because of its undesirable property of interacting with high affinity and in a non-immune manner with the Fc region of human IgA. Truncated forms of the beta antigen are secreted by certain strains of GBS in the absence of cell surface expression of the antigen, and both IgA Fc binding and non-binding forms are observed (Brady et at, 1989).
There is evidence that high levels of maternal antibodies against GBS can be passed to and protect the newborn via the placenta. Therefore, there is a great deal of interest in developing a maternal GBS vaccine. Although the beta antigen is known to be immunogenic (i.e., it induces the formation of protective antibodies) in rabbits and mice, it would be dangerous to include in a human vaccine component which can bind to a human protein.
Therefore, an object of the subject invention is to provide a non-IgA Fc binding form of the beta antigen of GBS.